Comparison of Orthogonal Determination Methods of Acid/Base Constants with Meta-Analysis
Abstract
1. Introduction
2. Materials and Methods
2.1. Data Collection
2.2. Statistical Analysis and Mathematical Calculations
3. Results
4. Discussion
4.1. Agreement Between Methods
4.2. Error Distribution and Methodological Differences
4.3. Mixed-Effects Models
4.4. Implications and Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Potentiometry | NMR/pH Titration | |
---|---|---|
Principle | Measurement of electrode potential at each degree of titration | Measurement of (usually) chemical shifts, which change with pH |
Accuracy | Very accurate, especially for systems with clear ion selectivity; inert atmosphere required but limited mainly to the 2–12 pH range | Very accurate, especially for complex molecules. Inert atmosphere can be avoided, and detectable pH range can be extended with in situ pH indicators [8] |
Complexity | Simple; requires calibration and maintenance of the electrodes | More complex NMR measurements needed. Isotope effect of the solvent may need to be accounted for |
Sample requirements | Sample must be pure (>95%) and of sufficient concentration (0.1–10 mmol/L) | Sample must be in sufficient concentration (>1 mmol/L) for NMR detection (some impurities may be present) |
Time, efficiency, throughput | Fast, especially for automated instruments, medium throughput | Slow, due to multiple scans and data interpretations. Low throughput; can be made faster and medium throughput using autosampler |
Cost | Low cost, simple instruments | Expensive, due to high equipment cost and maintenance |
Titration of multiprotic molecules | Characterizes the molecule as a whole, in the case of overlapping protonation steps as well | Provides information on specific protonation sites |
Compound | Step | NMR pKa | Pot. pKa | NMR Std. Err. | Pot. Std. Err. | Study | t (°C) | I (mol/L) |
---|---|---|---|---|---|---|---|---|
oxidized glutathione | 1 | 1.79 | 1.6 | ±0.02 | ±0.1 | [37] | 25 | 0.15 |
oxidized glutathione | 2 | 2.42 | 2.32 | ±0.02 | ±0.03 | [37] | 25 | 0.15 |
oxidized glutathione | 3 | 3.23 | 3.15 | ±0.02 | ±0.02 | [37] | 25 | 0.15 |
oxidized glutathione | 4 | 3.92 | 3.85 | ±0.02 | ±0.01 | [37] | 25 | 0.15 |
oxidized glutathione | 5 | 8.95 | 8.83 | ±0.02 | ±0.01 | [37] | 25 | 0.15 |
oxidized glutathione | 6 | 9.71 | 9.53 | ±0.01 | ±0.02 | [37] | 25 | 0.15 |
Original Mixed-Effects Model | Extended Mixed-Effects Model with Variance Structure |
---|---|
AIC = 1098.627 | AIC = 1093.463 |
BIC = 1118.659 | BIC = 1117.501 |
LogLik = –544.3134 | LogLik = –540.7316 |
Random effects: | Random effects: |
Formula: ~1|compound | Formula: ~1|compound |
intercept sd: 1.313 | intercept sd: 1.313 |
Formula: ~1|step in compound | Formula: ~1|step in compound |
intercept sd: 3.031 | intercept sd: 3.032 |
residual sd: 0.209 | residual sd: 0.1614 |
Fixed effects (value, std.error, t-value): | Fixed effects (value, std.error, t-value): |
intercept: | Intercept: |
6.66, 0.26, 25.8669 | 6.67, 0.26, 25.8959 |
Effect of method (NMR): | Effect of method (NMR): |
0.062, 0.022, 2.8751 | 0.041, 0.021, 1.9611 |
Degrees of freedom = 213 | Degrees of freedom = 213 |
Correlation of intercept~NMR: –0.042 | Correlation of intercept~NMR: –0.04 Variance parameter estimate: 0.0339 |
ANOVA (F-value, p-value) | ANOVA (F-value, p-value) |
intercept: | intercept: |
676.5005, <0.0001 | 675.7902, <0.0001 |
method: | method: |
8.2662, 0.0044 | 3.8461, 0.0512 |
RNH2 | R2NH | R3N | ROH | RCOR | RCOOH | RCOOR | ROR | RCCH | Rings | Arom |
---|---|---|---|---|---|---|---|---|---|---|
30 | 19 | 26 | 34 | 11 | 49 | 10 | 24 | 1 | 61 | 59 |
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Pálla, T.; Mazák, K.; Alkhazragee, D.M.; Balogh, G.T.; Noszál, B.; Mirzahosseini, A. Comparison of Orthogonal Determination Methods of Acid/Base Constants with Meta-Analysis. Int. J. Mol. Sci. 2024, 25, 12727. https://doi.org/10.3390/ijms252312727
Pálla T, Mazák K, Alkhazragee DM, Balogh GT, Noszál B, Mirzahosseini A. Comparison of Orthogonal Determination Methods of Acid/Base Constants with Meta-Analysis. International Journal of Molecular Sciences. 2024; 25(23):12727. https://doi.org/10.3390/ijms252312727
Chicago/Turabian StylePálla, Tamás, Károly Mazák, Dania Mohammed Alkhazragee, György Tibor Balogh, Béla Noszál, and Arash Mirzahosseini. 2024. "Comparison of Orthogonal Determination Methods of Acid/Base Constants with Meta-Analysis" International Journal of Molecular Sciences 25, no. 23: 12727. https://doi.org/10.3390/ijms252312727
APA StylePálla, T., Mazák, K., Alkhazragee, D. M., Balogh, G. T., Noszál, B., & Mirzahosseini, A. (2024). Comparison of Orthogonal Determination Methods of Acid/Base Constants with Meta-Analysis. International Journal of Molecular Sciences, 25(23), 12727. https://doi.org/10.3390/ijms252312727